Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort.

Waszak, Sebastian M; von Hoff, Katja; Ernst, Aurelie; Morrissy, A Sorana; Shelagh, Redmond; Bustamante, Carlos D; Zichner, Thomas; Pfister, Stefan; Hassall, Timothy; Solomon, David A; Perry, Arie; Eggen, Tone; Jabado, Nada; Bendel, Anne E; Kjaerheim, Kristina; Northcott, Paul A; Gilbertson, Richard J; Sutter, Christian; Mardin, Balca R; Jones, David; Hauser, Peter; Chavez, Lukas; Frank, Stephan; Duke, Elizabeth; MacDonald, Tobey J; Korshunov, Andrey; Grund, Kerstin B; Hernáiz Driever, Pablo; Weischenfeldt, Joachim; Kool, Marcel; Pajtler, Kristian; Taylor, Michael D; Ryzhova, Marina V; Bowers, Daniel C; Brugières, Laurence; Chintagumpala, Murali M; Röösli, Martin; Baciu, Cristina; Rausch, Tobias; Sumerauer, David; Cohn, Richard; Varlet, Pascale; Grajkowska, Wiesława; Ng, Ho-Keung; Hain, Michael; Lannering, Birgitta; Zitterbart, Karel; Zhou, Xin; Samuel, David; Marra, Marco; Feychting, Maria; Gajjar, Amar; Malkin, David; Johansen, Christoffer; Grotzer, Michael; Groebner, Susanne; Brabetz, Sebastian; Bartram, Claus R; Lawerenz, Christian; Guerrini-Rousseau, Lea; Robinson, Giles W; Fleischhack, Gudrun; Andersen, Tina V; Fults, Daniel W; De La Vega, Francisco M; Archer, Tenley C; Schüz, Joachim; Buchhalter, Ivo; Shringarpure, Suyash S; Kuehni, Claudia E; Milde, Till; McCowage, Geoffrey; Rutkowski, Stefan; Ra, Young-Shin; Zhang, Jinghui; Korbel, Jan O; Eils, Roland; Segura-Wang, Maia; Lichter, Peter; Scheurlen, Wolfram; Monoranu, Camelia M; Pomeroy, Scott L; Chan, Jennifer A; Ramaswamy, Vijay; Wesenberg, Finn; Sturm, Dominik; Kratz, Christian P

doi:10.1016/S1470-2045(18)30242-0

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000135972 0247_ $$2doi$$a10.1016/S1470-2045(18)30242-0
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000135972 0247_ $$2ISSN$$a1474-5488
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000135972 037__ $$aDKFZ-2018-00708
000135972 041__ $$aeng
000135972 082__ $$a610
000135972 1001_ $$aWaszak, Sebastian M$$b0
000135972 245__ $$aSpectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort.
000135972 260__ $$aLondon$$bThe Lancet Publ. Group$$c2018
000135972 3367_ $$2DRIVER$$aarticle
000135972 3367_ $$2DataCite$$aOutput Types/Journal article
000135972 3367_ $$0PUB:(DE-HGF)16$$2PUB:(DE-HGF)$$aJournal Article$$bjournal$$mjournal$$s1660207438_9214
000135972 3367_ $$2BibTeX$$aARTICLE
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000135972 520__ $$a<?xml version='1.0' encoding='UTF-8'?><html xmlns:m='http://www.w3.org/1998/Math/MathML' xmlns:mml='http://www.w3.org/1998/Math/MathML' xmlns:math='http://www.w3.org/1998/Math/MathML'> Medulloblastoma is associated with rare hereditary cancer predisposition syndromes; however, consensus medulloblastoma predisposition genes have not been defined and screening guidelines for genetic counselling and testing for paediatric patients are not available. We aimed to assess and define these genes to provide evidence for future screening guidelines.In this international, multicentre study, we analysed patients with medulloblastoma from retrospective cohorts (International Cancer Genome Consortium [ICGC] PedBrain, Medulloblastoma Advanced Genomics International Consortium [MAGIC], and the CEFALO series) and from prospective cohorts from four clinical studies (SJMB03, SJMB12, SJYC07, and I-HIT-MED). Whole-genome sequences and exome sequences from blood and tumour samples were analysed for rare damaging germline mutations in cancer predisposition genes. DNA methylation profiling was done to determine consensus molecular subgroups: WNT (MBWNT), SHH (MBSHH), group 3 (MBGroup3), and group 4 (MBGroup4). Medulloblastoma predisposition genes were predicted on the basis of rare variant burden tests against controls without a cancer diagnosis from the Exome Aggregation Consortium (ExAC). Previously defined somatic mutational signatures were used to further classify medulloblastoma genomes into two groups, a clock-like group (signatures 1 and 5) and a homologous recombination repair deficiency-like group (signatures 3 and 8), and chromothripsis was investigated using previously established criteria. Progression-free survival and overall survival were modelled for patients with a genetic predisposition to medulloblastoma.We included a total of 1022 patients with medulloblastoma from the retrospective cohorts (n=673) and the four prospective studies (n=349), from whom blood samples (n=1022) and tumour samples (n=800) were analysed for germline mutations in 110 cancer predisposition genes. In our rare variant burden analysis, we compared these against 53 105 sequenced controls from ExAC and identified APC, BRCA2, PALB2, PTCH1, SUFU, and TP53 as consensus medulloblastoma predisposition genes according to our rare variant burden analysis and estimated that germline mutations accounted for 6% of medulloblastoma diagnoses in the retrospective cohort. The prevalence of genetic predispositions differed between molecular subgroups in the retrospective cohort and was highest for patients in the MBSHH subgroup (20% in the retrospective cohort). These estimates were replicated in the prospective clinical cohort (germline mutations accounted for 5% of medulloblastoma diagnoses, with the highest prevalence [14%] in the MBSHH subgroup). Patients with germline APC mutations developed MBWNT and accounted for most (five [71%] of seven) cases of MBWNT that had no somatic CTNNB1 exon 3 mutations. Patients with germline mutations in SUFU and PTCH1 mostly developed infant MBSHH. Germline TP53 mutations presented only in childhood patients in the MBSHH subgroup and explained more than half (eight [57%] of 14) of all chromothripsis events in this subgroup. Germline mutations in PALB2 and BRCA2 were observed across the MBSHH, MBGroup3, and MBGroup4 molecular subgroups and were associated with mutational signatures typical of homologous recombination repair deficiency. In patients with a genetic predisposition to medulloblastoma, 5-year progression-free survival was 52% (95% CI 40-69) and 5-year overall survival was 65% (95% CI 52-81); these survival estimates differed significantly across patients with germline mutations in different medulloblastoma predisposition genes.Genetic counselling and testing should be used as a standard-of-care procedure in patients with MBWNT and MBSHH because these patients have the highest prevalence of damaging germline mutations in known cancer predisposition genes. We propose criteria for routine genetic screening for patients with medulloblastoma based on clinical and molecular tumour characteristics.German Cancer Aid; German Federal Ministry of Education and Research; German Childhood Cancer Foundation (Deutsche Kinderkrebsstiftung); European Research Council; National Institutes of Health; Canadian Institutes for Health Research; German Cancer Research Center; St Jude Comprehensive Cancer Center; American Lebanese Syrian Associated Charities; Swiss National Science Foundation; European Molecular Biology Organization; Cancer Research UK; Hertie Foundation; Alexander and Margaret Stewart Trust; V Foundation for Cancer Research; Sontag Foundation; Musicians Against Childhood Cancer; BC Cancer Foundation; Swedish Council for Health, Working Life and Welfare; Swedish Research Council; Swedish Cancer Society; the Swedish Radiation Protection Authority; Danish Strategic Research Council; Swiss Federal Office of Public Health; Swiss Research Foundation on Mobile Communication; Masaryk University; Ministry of Health of the Czech Republic; Research Council of Norway; Genome Canada; Genome BC; Terry Fox Research Institute; Ontario Institute for Cancer Research; Pediatric Oncology Group of Ontario; The Family of Kathleen Lorette and the Clark H Smith Brain Tumour Centre; Montreal Childrens Hospital Foundation
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000135972 7001_ $$0P:(DE-HGF)0$$aNorthcott, Paul A$$b1$$eFirst author
000135972 7001_ $$0P:(DE-He78)e84b3187ddd3529f884082e30f228c66$$aBuchhalter, Ivo$$b2
000135972 7001_ $$aRobinson, Giles W$$b3
000135972 7001_ $$aSutter, Christian$$b4
000135972 7001_ $$0P:(DE-HGF)0$$aGroebner, Susanne$$b5
000135972 7001_ $$aGrund, Kerstin B$$b6
000135972 7001_ $$aBrugières, Laurence$$b7
000135972 7001_ $$0P:(DE-He78)551bb92841f634070997aa168d818492$$aJones, David$$b8
000135972 7001_ $$0P:(DE-He78)a7c1bbac024fa232d9c6b78443328d9d$$aPajtler, Kristian$$b9
000135972 7001_ $$aMorrissy, A Sorana$$b10
000135972 7001_ $$0P:(DE-He78)4c28e2aade5f44d8eca9dd8e97638ec8$$aKool, Marcel$$b11
000135972 7001_ $$0P:(DE-He78)a46a5b2a871859c8e2d63d2f8c666807$$aSturm, Dominik$$b12
000135972 7001_ $$0P:(DE-He78)082dd3179733e3e716a58eb90f418a78$$aChavez, Lukas$$b13
000135972 7001_ $$0P:(DE-He78)509fb81813c1911954da583129e8ea57$$aErnst, Aurelie$$b14
000135972 7001_ $$0P:(DE-He78)b0b3740107f746e09dc23fdf25eb0629$$aBrabetz, Sebastian$$b15
000135972 7001_ $$0P:(DE-He78)6459d1855a83c1b05e4d47366d21ce67$$aHain, Michael$$b16
000135972 7001_ $$aZichner, Thomas$$b17
000135972 7001_ $$aSegura-Wang, Maia$$b18
000135972 7001_ $$aWeischenfeldt, Joachim$$b19
000135972 7001_ $$aRausch, Tobias$$b20
000135972 7001_ $$aMardin, Balca R$$b21
000135972 7001_ $$aZhou, Xin$$b22
000135972 7001_ $$aBaciu, Cristina$$b23
000135972 7001_ $$0P:(DE-He78)5398550c21bc4ce3b0ff670b04150334$$aLawerenz, Christian$$b24
000135972 7001_ $$aChan, Jennifer A$$b25
000135972 7001_ $$aVarlet, Pascale$$b26
000135972 7001_ $$aGuerrini-Rousseau, Lea$$b27
000135972 7001_ $$aFults, Daniel W$$b28
000135972 7001_ $$aGrajkowska, Wiesława$$b29
000135972 7001_ $$aHauser, Peter$$b30
000135972 7001_ $$aJabado, Nada$$b31
000135972 7001_ $$aRa, Young-Shin$$b32
000135972 7001_ $$aZitterbart, Karel$$b33
000135972 7001_ $$aShringarpure, Suyash S$$b34
000135972 7001_ $$aDe La Vega, Francisco M$$b35
000135972 7001_ $$aBustamante, Carlos D$$b36
000135972 7001_ $$aNg, Ho-Keung$$b37
000135972 7001_ $$aPerry, Arie$$b38
000135972 7001_ $$aMacDonald, Tobey J$$b39
000135972 7001_ $$aHernáiz Driever, Pablo$$b40
000135972 7001_ $$aBendel, Anne E$$b41
000135972 7001_ $$aBowers, Daniel C$$b42
000135972 7001_ $$aMcCowage, Geoffrey$$b43
000135972 7001_ $$aChintagumpala, Murali M$$b44
000135972 7001_ $$aCohn, Richard$$b45
000135972 7001_ $$aHassall, Timothy$$b46
000135972 7001_ $$aFleischhack, Gudrun$$b47
000135972 7001_ $$aEggen, Tone$$b48
000135972 7001_ $$aWesenberg, Finn$$b49
000135972 7001_ $$aFeychting, Maria$$b50
000135972 7001_ $$aLannering, Birgitta$$b51
000135972 7001_ $$aSchüz, Joachim$$b52
000135972 7001_ $$aJohansen, Christoffer$$b53
000135972 7001_ $$aAndersen, Tina V$$b54
000135972 7001_ $$aRöösli, Martin$$b55
000135972 7001_ $$aKuehni, Claudia E$$b56
000135972 7001_ $$aGrotzer, Michael$$b57
000135972 7001_ $$aKjaerheim, Kristina$$b58
000135972 7001_ $$aMonoranu, Camelia M$$b59
000135972 7001_ $$aArcher, Tenley C$$b60
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000135972 7001_ $$aPomeroy, Scott L$$b62
000135972 7001_ $$aShelagh, Redmond$$b63
000135972 7001_ $$aFrank, Stephan$$b64
000135972 7001_ $$aSumerauer, David$$b65
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000135972 7001_ $$aRyzhova, Marina V$$b67
000135972 7001_ $$0P:(DE-He78)0be2f86573954f87e97f8a4dbb05cb0f$$aMilde, Till$$b68
000135972 7001_ $$aKratz, Christian P$$b69
000135972 7001_ $$aSamuel, David$$b70
000135972 7001_ $$aZhang, Jinghui$$b71
000135972 7001_ $$aSolomon, David A$$b72
000135972 7001_ $$aMarra, Marco$$b73
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000135972 7001_ $$avon Hoff, Katja$$b76
000135972 7001_ $$aRutkowski, Stefan$$b77
000135972 7001_ $$aRamaswamy, Vijay$$b78
000135972 7001_ $$aGilbertson, Richard J$$b79
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000135972 7001_ $$aKorbel, Jan O$$b85
000135972 7001_ $$0P:(DE-He78)f746aa965c4e1af518b016de3aaff5d9$$aPfister, Stefan$$b86$$eLast author
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